Uveal melanoma is the most common and malignant intraocular tumor in adults. Metastases appear in 19% to 35% of the patients within 5 years of diagnosis of uveal melanoma. The liver is the primary organ for the development of metastases, and up to 95% of the patients who die from uveal melanoma have liver metastases at the time of death. Although the treatment for primary uveal melanoma has improved substantially over the past two decades, there have been no significant advances in the management of metastases and as such, the five-year survival time for uveal melanoma patients has not changed in over 30 years. Regrettably, there still remains no effective treatment for uveal melanoma metastases. This Research Plan addresses four specific aims relating to the immunobiology of uveal melanoma and the development of liver metastases.
The first aim will test the hypothesis that primary uveal melanoma expresses a chemokine receptor (i.e., CXCR4), that contributes to the organ-specific development of liver metastases. However, unlike other tumors that metastasize to the liver, such as colon cancer, uveal melanoma cells down regulate their CXCR4 expression after colonizing the liver.
The second aim will test the hypothesis that two novel T cell populations, one expressing the gamma/delta T cell receptor (gamma/delta Tcells) and the other expressing natural killer (NK) markers, play important roles in controlling the development of liver metastases arising from intraocular melanomas.
The third aim will test the hypothesis that uveal melanoma cells and their metastases elaborate indoleamine dioxygenase (IDO), a potent immunosuppressive molecule, which might serve as an escape mechanism for eluding T cell-mediated immune surveillance.
The fourth aim will evaluate the therapeutic efficacy of a monoclonal antibody directed against human CD54 in controlling liver metastases in a nude mouse model of uveal melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030276-29
Application #
7800332
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Yovandich, Jason L
Project Start
1981-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
29
Fiscal Year
2010
Total Cost
$287,239
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Han, Zhiqiang; Brown, Joseph R; Niederkorn, Jerry Y (2016) Growth and Metastasis of Intraocular Tumors in Aged Mice. Invest Ophthalmol Vis Sci 57:2366-76
Sadegh, Leila; Chen, Peter W; Brown, Joseph R et al. (2015) NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases. Int J Cancer 137:1085-94
Niederkorn, Jerry Y (2013) Corneal transplantation and immune privilege. Int Rev Immunol 32:57-67
Li, Haochuan; Niederkorn, Jerry Y; Sadegh, Leila et al. (2013) Epigenetic regulation of CXCR4 expression by the ocular microenvironment. Invest Ophthalmol Vis Sci 54:234-43
Yang, Wanhua; Li, Haochuan; Mayhew, Elizabeth et al. (2011) NKT cell exacerbation of liver metastases arising from melanomas transplanted into either the eyes or spleens of mice. Invest Ophthalmol Vis Sci 52:3094-102
Li, Haochuan; Yang, Wanhua; Chen, Peter W et al. (2009) Inhibition of chemokine receptor expression on uveal melanomas by CXCR4 siRNA and its effect on uveal melanoma liver metastases. Invest Ophthalmol Vis Sci 50:5522-8
Niederkorn, Jerry Y (2009) Immune escape mechanisms of intraocular tumors. Prog Retin Eye Res 28:329-47
Yang, Wanhua; Li, Haochuan; Chen, Peter W et al. (2009) PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation. Invest Ophthalmol Vis Sci 50:273-80
Li, Haochuan; Alizadeh, Hassan; Niederkorn, Jerry Y (2008) Differential expression of chemokine receptors on uveal melanoma cells and their metastases. Invest Ophthalmol Vis Sci 49:636-43
Yang, Wanhua; Chen, Peter W; Li, Haochuan et al. (2008) PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci 49:2518-25

Showing the most recent 10 out of 51 publications